Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner

Abstract

Sulfonylurea receptors (SURs) constitute the regulatory subunits of ATP-sensitive K+ channels (KATP channels). SUR binds nucleotides and synthetic KATP channel modulators, e.g. the antidiabetic sulfonylurea glibenclamide, which acts as a channel blocker. However, knowledge about naturally occurring ligands of SUR is very limited. In this study, we show that the plant phenolic compound trans-resveratrol can bind to SUR and displace binding of glibenclamide. Electrophysiological measurements revealed that resveratrol is a blocker of pancreatic SUR1/KIR6.2 KATP channels. We further demonstrate that, like glibenclamide, resveratrol induces enhanced apoptosis. This was shown by analyzing different apoptotic parameters (cell detachment, nuclear condensation and fragmentation, and activities of different caspase enzymes). The observed apoptotic effect was specific to cells expressing the SUR1 isoform and was not mediated by the electrical activity of KATP channels, as it was observed in human embryonic kidney 293 cells expressing SUR1 alone. Enhanced susceptibility to resveratrol was not observed in pancreatic β-cells from SUR1 knock-out mice or in cells expressing the isoform SUR2A or SUR2B or the mutant SUR1(M1289T). Resveratrol was much more potent than glibenclamide in inducing SUR1-specific apoptosis. Treatment with etoposide, a classical inducer of apoptosis, did not result in SUR isoform-specific apoptosis. In conclusion, resveratrol is a natural SUR ligand that can induce apoptosis in a SUR isoform-specific manner. Considering the tissue-specific expression patterns of SUR isoforms and the possible effects of SUR mutations on susceptibility to apoptosis, these observations could be important for diabetes and/or cancer research. Sulfonylurea receptors (SURs) constitute the regulatory subunits of ATP-sensitive K+ channels (KATP channels). SUR binds nucleotides and synthetic KATP channel modulators, e.g. the antidiabetic sulfonylurea glibenclamide, which acts as a channel blocker. However, knowledge about naturally occurring ligands of SUR is very limited. In this study, we show that the plant phenolic compound trans-resveratrol can bind to SUR and displace binding of glibenclamide. Electrophysiological measurements revealed that resveratrol is a blocker of pancreatic SUR1/KIR6.2 KATP channels. We further demonstrate that, like glibenclamide, resveratrol induces enhanced apoptosis. This was shown by analyzing different apoptotic parameters (cell detachment, nuclear condensation and fragmentation, and activities of different caspase enzymes). The observed apoptotic effect was specific to cells expressing the SUR1 isoform and was not mediated by the electrical activity of KATP channels, as it was observed in human embryonic kidney 293 cells expressing SUR1 alone. Enhanced susceptibility to resveratrol was not observed in pancreatic β-cells from SUR1 knock-out mice or in cells expressing the isoform SUR2A or SUR2B or the mutant SUR1(M1289T). Resveratrol was much more potent than glibenclamide in inducing SUR1-specific apoptosis. Treatment with etoposide, a classical inducer of apoptosis, did not result in SUR isoform-specific apoptosis. In conclusion, resveratrol is a natural SUR ligand that can induce apoptosis in a SUR isoform-specific manner. Considering the tissue-specific expression patterns of SUR isoforms and the possible effects of SUR mutations on susceptibility to apoptosis, these observations could be important for diabetes and/or cancer research. Sulfonylurea receptors (SURs) 2The abbreviations used are: SUR(s), sulfonylurea receptor(s); DIDS, 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid; HEK, human embryonic kidney; SUR1KO, SUR1 knock-out; AFC, 7-amino-4-trifluoromethylcoumarin. are members of the ATP-binding cassette protein family (subfamily C). SURs are known to be the important regulatory subunits of ATP-sensitive K+ channels (KATP channels). These channels are heteromeric complexes composed of four SUR subunits that surround a central pore formed by four subunits from the KIR6.x family. KATP channels found in various tissues exhibit distinct physiological and pharmacological properties because of the combination of different subunit isoforms (reviewed in Ref. 1Aguilar-Bryan L. Bryan J. Endocr. Rev. 1999; 20: 101-135Crossref PubMed Scopus (624) Google Scholar). In addition to two nucleotide-binding domains, SUR possesses binding sites for synthetic KATP channel modulators. The binding sites for blockers and openers are different, but they are linked via complex allosteric interactions (2Bray K.M. Quast U. J. Biol. Chem. 1992; 267: 11689-11692Abstract Full Text PDF PubMed Google Scholar, 3Schwanstecher M. Brandt C. Behrends S. Schaupp U. Panten U. Br. J. Pharmacol. 1992; 106: 295-301Crossref PubMed Scopus (56) Google Scholar). Because of their nucleotide sensitivity, KATP channels couple the energy metabolism of a cell to the membrane potential. This is important in the pancreatic β-cell, in which closure of KATP channels triggers insulin secretion via membrane depolarization in response to changes in blood glucose levels (4Ashcroft S.J.H. J. Membr. Biol. 2000; 176: 187-206Crossref PubMed Scopus (70) Google Scholar, 5Gribble F.M. Reimann F. Diabetologia. 2003; 46: 875-891Crossref PubMed Scopus (253) Google Scholar, 6Bryan J. Vila-Carriles W.H. Zhao G. Babenko A.P. Aguilar-Bryan L. Diabetes. 2004; 53: S104-S112Crossref PubMed Scopus (94) Google Scholar). KATP channel-blocking drugs such as the sulfonylureas and the glinides can promote insulin secretion and are used in the treatment of diabetes type 2. Insulin secretion is also modulated and amplified by other pathways within the β-cell that are, in general, KATP channel-independent (7Doyle M.E. Egan J.M. Pharmacol. Rev. 2003; 55: 105-131Crossref PubMed Scopus (200) Google Scholar, 8Henquin J.C. Diabetes. 2004; 53: S48-S58Crossref PubMed Scopus (107) Google Scholar). In addition, the extent of insulin secretion is also influenced by adaptive variation of the total number of β-cells. It has been observed that β-cell mass is often increased in obese non-diabetic patients and is significantly reduced in patients suffering from diabetes type 2 (9Butler A.E. Janson J. Bonner-Weir S. Ritzel R. Rizza R.A. Butler P.C. Diabetes. 2003; 52: 102-110Crossref PubMed Scopus (3330) Google Scholar). Changes in β-cell mass can be achieved via controlled proliferation or apoptosis, but the molecular mechanisms are unknown (10Efanova I.B. Zaitsev S.V. Zhivotovsky B. Kohler M. Efendić S. Orrenius S. Berggren P.O. J. Biol. Chem. 1998; 273: 33501-33507Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 11Mandrup-Poulsen T. Diabetes. 2001; 50: S58-S63Crossref PubMed Google Scholar, 12Donath M.Y. Ehses J.A. Maedler K. Schumann D.M. Ellingsgaard H. Eppler E. Reinecke M. Diabetes. 2005; 54: S108-S113Crossref PubMed Scopus (383) Google Scholar, 13Ahrén B. Curr. Mol. Med. (Hilversum). 2005; 5: 275-286Crossref PubMed Scopus (118) Google Scholar). In several studies, it has been shown that the sulfonylurea compounds glibenclamide and tolbutamide can induce apoptosis in β-cells or clonal β-cell lines under certain conditions (10Efanova I.B. Zaitsev S.V. Zhivotovsky B. Kohler M. Efendić S. Orrenius S. Berggren P.O. J. Biol. Chem. 1998; 273: 33501-33507Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 14Iwakura T. Fujimoto S. Kagimoto S. Inada A. Kubota A. Someya Y. Ihara Y. Yamada Y. Seino Y. Biochem. Biophys. Res. Commun. 2000; 271: 422-428Crossref PubMed Scopus (54) Google Scholar, 15Rustenbeck I. Krautheim A. Jörns A. Steinfelder H.J. Biochem. Pharmacol. 2004; 67: 1733-1741Crossref PubMed Scopus (21) Google Scholar, 16Maedler K. Størling J. Sturis J. Zuellig R.A. Spinas G.A. Arkhammar P.O.G. Mandrup-Poulsen T. Donath M.Y. Diabetes. 2004; 53: 1706-1713Crossref PubMed Scopus (140) Google Scholar, 17Maedler K. Carr R.D. Bosco D. Zuellig R.A. Berney T. Donath M.Y. J. Clin. 2005; PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar). The mechanisms this cell not been and in for treatment with to be a cell we shown that expression of the pancreatic isoform SUR1 can cells more to apoptosis A. C. S. H. J. Pharmacol. PubMed Scopus Google Scholar). This effect was not observed in cells expressing the isoform SUR2B or the mutant in which a in the was with the of The of this was to SUR1-specific cell can be by more potent apoptotic than glibenclamide. We that trans-resveratrol is a ligand of SUR to induce SUR1-specific apoptosis to glibenclamide. In addition to several other physiological resveratrol has been shown to apoptosis under certain on cell type and Resveratrol is in and plant e.g. in and and as a it is in in response to such as S. 2004; PubMed Scopus Google Scholar, I. Mol. Res. 2005; PubMed Scopus Google Scholar, E. Mol. Res. 2005; PubMed Scopus Google Scholar). Resveratrol is to DIDS, a synthetic KATP channel that binds to SUR T. L. T. M. J. Membr. Biol. PubMed Scopus Google Scholar, F.M. Br. J. Pharmacol. 2001; PubMed Scopus Google Scholar, L. A. C. Quast U. U. Br. J. Pharmacol. PubMed Scopus Google Scholar). Resveratrol is to with several ATP-binding cassette cancer T. Biochem. Biophys. Res. Commun. 2004; PubMed Scopus Google B. M.E. H. J. 2000; PubMed Google and protein C. A. R. S. J.M. J. Chem. 2005; 53: PubMed Scopus Google Scholar, T. S. A. S. L. C. Y. 2005; PubMed Scopus Google and with several different ATP-binding cassette I. Mol. 2003; PubMed Scopus Google Scholar, H. Mol. 2001; PubMed Scopus Google Scholar, R. H. J. K. T. Mol. 267: PubMed Scopus (70) Google Scholar). from the knowledge about naturally occurring ligands of SUR very limited. It has been observed that as natural to the sulfonylurea compounds D. L. A. K. A. L. Mol. 1999; PubMed Scopus Google and that certain can with binding of synthetic channel A. J. D. Quast U. Br. J. Pharmacol. 2005; PubMed Scopus Google Scholar). that resveratrol is a ligand of SUR and to binding properties with of glibenclamide, we binding with from human embryonic kidney 293 cells expressing different SUR In these was used as the and resveratrol as the Electrophysiological on β-cells to show that resveratrol pancreatic SUR1/KIR6.2 channels. The apoptotic of resveratrol was in cells expressing SUR2A and or SUR1(M1289T). The of the expression of the KATP channel for apoptosis was in cells with or of The apoptotic of resveratrol was by different apoptotic parameters (cell detachment, nuclear fragmentation, and Because of the of different apoptotic cell we also the activities of caspase and to the possible of a specific The apoptotic effect of resveratrol was with that of etoposide, the of which is not by SUR1 expression A. C. S. H. J. Pharmacol. PubMed Scopus Google Scholar). In this the of resveratrol as a for a possible for β-cell apoptosis is cell lines with the expression the of SUR1 number SUR2A number SUR2B number or or they with the expression The been from SUR1 or SUR2B the and the different cell lines and to A. C. S. H. J. Pharmacol. PubMed Scopus Google Scholar). of cells as A. C. S. H. J. Pharmacol. PubMed Scopus Google Scholar). The cell lines and SUR1/KIR6.2 and from These cells in and or in glucose and in the of and The cells in a of and and a of on pancreatic of from mice or from SUR1 knock-out mice M. F. Aguilar-Bryan L. Bryan J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). from or mice and by of the the in 2 and Treatment with Resveratrol or cell or and cells with resveratrol or by addition of or of a resveratrol in or or in to of In or of was of cells or of was was in two of of and cells with a to A. C. S. H. J. Pharmacol. PubMed Scopus Google Scholar). from the of for The cells with the cell was and in of and apoptotic of or cells by in was of from and to A. C. S. H. J. Pharmacol. PubMed Scopus Google Scholar). the of condensation and fragmentation, the number of total and apoptotic cells HEK, or cells or was This was within the cell or the in different treatment of the of The activities of different caspase by of specific or to the and by with a activities as in and to the protein of the of the different caspase of the by other with be of a specific to the activities of of and cells and as by A. C. S. H. J. Pharmacol. PubMed Scopus Google and in a total of activity was a to the in a total of The protein in the and and of resveratrol to different SUR was in as the and and and Resveratrol was in and as the from the cell lines and membrane and membrane and membrane in the of for and binding properties as by A. T. D. H. Diabetes. 2004; 53: PubMed Scopus Google Scholar). binding of was in the of glibenclamide or in from Electrophysiological on pancreatic β-cells and of and with was The of 2 and with cell KATP channel and a of and to and with a of with The β-cells by of pancreatic in and with from two different cell used for of as from and of in combination with as The the of the the extent of is the is the of the with and is the of the compound under study, with The by for the of the to the is the of the of the to the to the of the of binding the parameters from and that and A. Pharmacol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). was from other used for cell or molecular from glibenclamide, and resveratrol from and caspase from caspase was from and was from and from of SUR Resveratrol the effects of resveratrol of on cells with different of SUR or on cells The of was to be to the of these with of other with the of glibenclamide A. C. S. H. J. Pharmacol. PubMed Scopus Google or to effects a and to or these effects by effects such as cell of and of cell was enhanced by in cells expressing SUR1 not SUR2B or the mutant with of cells expressing SUR2B or to be but not significantly than that of observed in cells expressing the SUR2A isoform resveratrol treatment with or and cell of cells was significantly than that of cells of the SUR2B SUR2A resveratrol SUR2A resveratrol SUR1 Treatment with also in cell but the cell and was not enhanced by SUR1 expression to the of the resveratrol and the revealed the of of and of cell cells and cells of resveratrol and these The number of cells to resveratrol for was with that observed treatment with resveratrol for and in Resveratrol treatment changes in with the of the cells and to their and treatment These of apoptosis very and in cells expressing but to a extent in cells or and cells apoptotic number of SUR1 SUR2B SUR2B SUR1 resveratrol SUR1 resveratrol SUR1 resveratrol In addition, of nuclear by a was observed resveratrol treatment not treatment also changes in nuclear but observed the different cell and the of nuclear was with that of cells resveratrol treatment not Changes in the of in Resveratrol activity of was significantly the cell lines in with changes in activity in the of the of the activity treatment to the activity of and with the activity of treatment was in cells and in SUR1 these not of activity was not and The activity of was resveratrol with in cells and The activity of was resveratrol but the cell lines and The activities of and also for and the cells and the other cell lines and and and of of SUR1 and on of the KATP channel has a effect on cell detachment, in which of and or of and cells to resveratrol for to in cell detachment, but was cells expressing SUR and cells SUR1 and of Resveratrol Treatment on and and in nuclear of cells to resveratrol that and which of apoptosis, the cells not the effects of resveratrol on the different cell the of apoptosis number of apoptotic number of in a of resveratrol treatment to apoptosis treatment was and In effects in the cell lines and In addition, the activity of was in and cells activity in cells resveratrol treatment was than treatment In activity in cells was resveratrol treatment than treatment of Resveratrol Treatment on from of from or mice and with resveratrol for In or and the number of apoptotic number of was significantly with that in However, pancreatic from mice with such in observed apoptotic number of from or knock-out mice with apoptotic changes observed and apoptotic number of which was in with the observations of M. F. Aguilar-Bryan L. Bryan J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google in their of of Resveratrol to SUR or In binding with used as the resveratrol to specific binding to from cells was In the of resveratrol glibenclamide binding to of with of The resveratrol binding properties of SUR1 not significantly different from for the mutant extent of The and the extent of from of the binding as under with to Resveratrol also to SUR2B and was to displace binding to with Because of the of SUR2B for a of binding parameters for resveratrol was not for SUR2B in this of further the of resveratrol with we also the mutant In this within the is with the of which to reduced glibenclamide of SUR1 R. F.M. S.J.H. F.M. Diabetes. 1999; PubMed Scopus Google Scholar). The of specific binding by resveratrol within the binding of to this mutant was reduced in with but with of total it was a of However, the SUR1-specific apoptotic effect of resveratrol was not reduced by the (cell of the SUR1 resveratrol SUR1 resveratrol The of which the glibenclamide of this SUR isoform A. C. U. U. Quast U. Mol. Pharmacol. Scopus (54) Google did not the of resveratrol to displace binding but increased the extent of to The susceptibility of cells to apoptosis was not with that of cells (cell of the resveratrol of Resveratrol on the with β-cells in the cell resveratrol significantly KATP under in the of and of Resveratrol the in a but to a extent with glibenclamide, which the of the KATP under and of the KATP of β-cell mass by apoptosis, and/or of pancreatic β-cells is important in pancreatic B. Curr. Mol. Med. (Hilversum). 2005; 5: 275-286Crossref PubMed Scopus (118) Google Scholar, 2005; PubMed Scopus Google Scholar). a of the mechanisms β-cell specific cell and knowledge about that can this are of It is known that β-cell for be by levels of glucose or several or of M.Y. Ehses J.A. Maedler K. Schumann D.M. Ellingsgaard H. Eppler E. Reinecke M. Diabetes. 2005; 54: S108-S113Crossref PubMed Scopus (383) Google Scholar, 13Ahrén B. Curr. Mol. Med. (Hilversum). 2005; 5: 275-286Crossref PubMed Scopus (118) Google Scholar, M. J.C. Jörns A. S. Diabetes. 2005; 54: PubMed Scopus Google Scholar). and induce β-cell via different mechanisms of and/or of these are often to diabetes in T. Res. 2001; 50: Scholar). Sulfonylurea drugs such as glibenclamide can also induce apoptosis in β-cells or β-cell lines under certain conditions (10Efanova I.B. Zaitsev S.V. Zhivotovsky B. Kohler M. Efendić S. Orrenius S. Berggren P.O. J. Biol. Chem. 1998; 273: 33501-33507Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 14Iwakura T. Fujimoto S. Kagimoto S. Inada A. Kubota A. Someya Y. Ihara Y. Yamada Y. Seino Y. Biochem. Biophys. Res. Commun. 2000; 271: 422-428Crossref PubMed Scopus (54) Google Scholar, 15Rustenbeck I. Krautheim A. Jörns A. Steinfelder H.J. Biochem. Pharmacol. 2004; 67: 1733-1741Crossref PubMed Scopus (21) Google Scholar, 16Maedler K. Størling J. Sturis J. Zuellig R.A. Spinas G.A. Arkhammar P.O.G. Mandrup-Poulsen T. Donath M.Y. Diabetes. 2004; 53: 1706-1713Crossref PubMed Scopus (140) Google Scholar, 17Maedler K. Carr R.D. Bosco D. Zuellig R.A. Berney T. Donath M.Y. J. Clin. 2005; PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar). However, the mechanisms this effect are not known In a study, we in a cell that expression of SUR1 cells more to apoptosis A. C. S. H. J. Pharmacol. PubMed Scopus Google that the SUR1 isoform could be in variation of β-cell mass and to of insulin secretion also this In this study, we shown that the naturally occurring which is known to induce cell in cell under certain can apoptotic effects that are to glibenclamide treatment A. C. S. H. J. Pharmacol. PubMed Scopus Google of cells to resveratrol a in different apoptotic parameters such as cell detachment, and of nuclear This of enhanced apoptosis not in cells which show a of apoptosis. The enhanced apoptotic effect resveratrol treatment is also not in or The SUR1-specific effect of resveratrol is by a in with the of as we observed for glibenclamide treatment A. C. S. H. J. Pharmacol. PubMed Scopus Google Scholar). However, the effect is not influenced by the within the with glibenclamide, resveratrol is much more potent in inducing effects are a of treatment with resveratrol than with glibenclamide of with etoposide, the effects of resveratrol on cells are more the effects of glibenclamide on these cells are In to resveratrol or glibenclamide, induces apoptotic (cell detachment, enhanced activity of or apoptotic changes in nuclear that not significantly the cell lines and that are not a further to glibenclamide, resveratrol SUR1-specific apoptosis in cells in the of the KATP channel This and the that the extent of apoptosis is not modulated by expression of that SUR1/KIR6.2 channels are not for the apoptotic This further for that SUR1 the electrical activity of KATP channels A. C. S. H. J. Pharmacol. PubMed Scopus Google Scholar). The SUR effect of resveratrol is not observed in the cell but is also the of cell or tissue-specific This was by the of of apoptosis in the β-cells lines and to resveratrol and by a different response of the cell which the SUR2B isoform U. F. E. A. Quast U. Br. J. Pharmacol. PubMed Scopus Google Scholar). from pancreatic from or mice further for the expression of SUR1 and enhanced of apoptosis. These the that SUR1-specific apoptosis is of expression in or and been to trans-resveratrol different molecular of and or of and of and been in with these different effects I. Mol. Res. 2005; PubMed Scopus Google Scholar, E. Mol. Res. 2005; PubMed Scopus Google Scholar, 2004; PubMed Scopus Google Scholar). The resveratrol to of these different effects in the been shown to from to or I. Mol. Res. 2005; PubMed Scopus Google Scholar). However, specific of resveratrol with SUR has been In addition to the apoptotic effect of we in binding that resveratrol binds to SUR and and is to displace specific binding of glibenclamide. that, like glibenclamide, resveratrol can as a blocker of the SUR1/KIR6.2 we further for In studies, a effect of resveratrol on or K+ channels was but for effect on KATP channels was Res. 2000; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. L. M. D. B. J. H. J. Pharmacol. PubMed Scopus Google Scholar). Because the subunit of KATP channels be in this a of channels different SUR isoforms could be of the of resveratrol for SUR1 is much than that of glibenclamide A. T. D. H. Diabetes. 2004; 53: PubMed Scopus Google which is also by to the pancreatic KATP resveratrol is much more in inducing apoptosis. the of for SUR and in inducing apoptosis This is by the that in the resveratrol or glibenclamide A. T. D. H. Diabetes. 2004; 53: PubMed Scopus Google binding properties of SUR1 and the mutant could be the expression of these different SURs is linked to a significantly different susceptibility to or apoptosis. the in which is for binding A. T. D. H. Diabetes. 2004; 53: PubMed Scopus Google and the effect C. H. M. J. 2000; PubMed Scopus Google of several KATP channel not a effect on binding of the blockers resveratrol and glibenclamide, but other important interactions within the SUR that are for cell the other the of resveratrol to displace glibenclamide binding to SUR1 is by the within the which is known to the glibenclamide of SUR1 R. F.M. S.J.H. F.M. Diabetes. 1999; PubMed Scopus Google SUR1-specific apoptosis is not influenced by this that the of the binding sites are not However, it is possible that a in the not resveratrol but allosteric interactions resveratrol and glibenclamide of the and a of the resveratrol binding and apoptosis by this be the of In of the that apoptotic effect of sulfonylureas (10Efanova I.B. Zaitsev S.V. Zhivotovsky B. Kohler M. Efendić S. Orrenius S. Berggren P.O. J. Biol. Chem. 1998; 273: 33501-33507Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 14Iwakura T. Fujimoto S. Kagimoto S. Inada A. Kubota A. Someya Y. Ihara Y. Yamada Y. Seino Y. Biochem. Biophys. Res. Commun. 2000; 271: 422-428Crossref PubMed Scopus (54) Google Scholar, 17Maedler K. Carr R.D. Bosco D. Zuellig R.A. Berney T. Donath M.Y. J. Clin. 2005; PubMed Scopus Google a of KATP channels and the cell is However, to I. Krautheim A. Jörns A. Steinfelder H.J. Biochem. Pharmacol. 2004; 67: 1733-1741Crossref PubMed Scopus (21) Google β-cell is not linked to the of these drugs to as KATP channel This is by that is not for the apoptotic effects of resveratrol or glibenclamide in the we the that SUR the apoptotic effect via with channel subunits other than of SUR1 or a protein with a channel has been for in J.M. J. 2004; PubMed Scopus (21) Google Scholar). a of SUR with other to specific of could also be the specific caspase activity we can the of the specific of activity in cells to resveratrol for of the apoptotic The activity of is not in the cell lines resveratrol treatment and the is not Enhanced activity is linked to which is often with effects on β-cell and M.Y. Ehses J.A. Maedler K. Schumann D.M. Ellingsgaard H. Eppler E. Reinecke M. Diabetes. 2005; 54: S108-S113Crossref PubMed Scopus (383) Google Scholar, M. J.C. Jörns A. S. Diabetes. 2005; 54: PubMed Scopus Google Scholar). The in activity in the cell lines not it be with the apoptotic effect of to of In addition to the effects achieved by of the in effects of be apoptosis, it is possible that in effects of resveratrol are achieved by than used in because a has shown that resveratrol is more in than in a cell E. Mol. Res. 2005; PubMed Scopus Google Scholar). In the of glibenclamide, which is potent in inducing SUR1-specific apoptosis than it has been shown that apoptotic effects in human are achieved treatment for K. Carr R.D. Bosco D. Zuellig R.A. Berney T. Donath M.Y. J. Clin. 2005; PubMed Scopus Google Scholar). Resveratrol is not of the human in of but is often as in the I. Mol. Res. 2005; PubMed Scopus Google or on the and metabolism of often it is that resveratrol is and to various of to 2 total resveratrol in of of (reviewed in I. Mol. Res. 2005; PubMed Scopus Google Scholar, E. Mol. Res. 2005; PubMed Scopus Google Scholar, and D. A. D. B. Curr. PubMed Scopus Google Scholar). from of the physiological of resveratrol as a or as a in in cancer or D. A. D. B. Curr. PubMed Scopus Google this compound to further the complex regulatory of In we shown that trans-resveratrol is a naturally occurring SUR ligand that several to the synthetic sulfonylurea glibenclamide binding to pancreatic KATP channels, and to induce apoptosis in a SUR manner. The effect not the of KATP channels. SUR1-specific of apoptosis to resveratrol is observed not in but also in β-cells. This of cell apoptosis could be important in diabetes as as cancer not because this apoptotic effect can be by a in of apoptosis is observed with specific with glibenclamide or but not with and it to be which of a possible SUR ligand are for the apoptotic We shown that a apoptotic is in apoptosis, but has to be to the of apoptosis and the of SUR in the We Aguilar-Bryan and Bryan for the mice and for and of the We are also to C. for the of SUR1 and Y. and Y. for the of the and We C. for in cell